Method of preparing biologically active formulations

ABSTRACT

The invention provides pellet for use as a core for a pharmaceutical dosage form having an inner and an outer zone where the inner zone includes a biologically active agent and said outer zone includes a layer formed by applying a substantially dry, free flowing inert powder which forms a non-tacky surface when placed in contact with water. The invention also provides a process for making pharmaceutical pellets where the core or at least one a layer on the core is formed by (a) contacting powder particles, adhering them to each other and compacting the adhered pellets by a rolling movement, wherein the degree of densification is controlled by the rolling movement; and (b) feeding a sufficient amount of a substantially dry, free flowing inert powder which forms a non-tacky surface when placed in contact with water to provide on said particles an outer zone including a layer formed from said substantially dry, free flowing inert powder.

[0001] The benefit of the filing date of Provisional Application SerialNo. 60/432,353, filed Dec. 10, 2002 is claimed.

BACKGROUND OF THE INVENTION

[0002] Oral solid dosage forms for biologically active agents have beenprepared using various techniques that have been used to combine apowdered biologically active agent substance with a diluent and to formthat mixture into a physical form that is suitable to make powder filledcapsules, compressible particles for making tablets or coatableparticles that are adapted for controlled release of active substancesusing matrix forming additives or membrane based controlled releasecoatings. As used herein, the term “biologically active agent” is usedto include pharmaceutical compounds, pharmaceutical compositions,vitamins and nutrients.

[0003] The prior art has used various wet granulation, dry granulation,fluidized-bed, extrusion-spheronization and direct compressiontechniques to prepare particles in the form of granules or pellets formaking solid dosage forms. In addition, spray-drying and spraycongealing techniques have been used to form these types of particles.

[0004] The use of fluidized beds has been based on the use of top-sprayor bottom-spray techniques using a Wurster air suspension column or atangential-spray in rotary fluid-bed coater/granulator. Apparatus whichhave been used for coating and/or making pellets are described in U.S.Pat. No. 4,895,733; U.S. Pat. No. 5,132,142 and U.S. Pat. No. 6,354,728all of which are incorporated by reference. South African patent20000169 describes certain pharmaceutical pelleted formulations whichcontain up to 90wt. % of a pharmaceutically active ingredient which aremade by conventional spheronization techniques.

[0005] As used herein the term “pellet” means a substantiallyspherically shaped particle having a aspect ratio (a ratio of the lengthof the pellet divided by the width found at an angle of 90° in respectto the length) which is less than about 1.4, more preferably less thanabout 1.3, even more preferably less than about 1.2, especiallypreferably less than about 1.1, and most preferably less than about1.05.

[0006] In one aspect, the present invention comprises the use of arotating device that propels the powder particles onto a tangentiallyarranged surface which causes the powder particles to roll on saidtangentially arranged surface. This process results in pellets having acontrolled density, for instance highly dense pellets. These pellets maybe formulated to have matrix controlled release properties or othertypes of release properties depending on the excipients which areemployed. The pellets may be: adapted to contain high levels ofbiologically active agents, i.e. more than 90wt %, such as more than95wt % and in particular more than 99wt % and even more than 99.9wt % ofa biologically active agent in each pellet; pellets that are directlymanufactured with a narrow size distribution without the need to carryout any substantial separation step and pellets that have multiplebiologically active agent and/or rate release controlling coatings whichwill provide for controlled release of the active agents and/or physicalseparation of incompatible agents that are advantageously administeredin combination. The pellet may comprise sustained release, pulsatilerelease, enteric release, immediate release or a combination of theserelease characteristics. In addition, the present invention providesnovel processing methods which can optionally be used to reduce oreliminate the use of organic solvents, can produce smaller particles,can reduce the number of process steps and increase the total throughputper operating unit due to greatly reduced processing cycles.

SUMMARY OF THE INVENTION

[0007] The invention provides novel pellets adapted for biologicallyactive preparations and a novel process for preparing said pellets. Thepellets comprise a core and optionally one or more than one layersurrounding the core. The core and/or at least one layer is formed frompowder particles.

[0008] The process of the invention comprises contacting of powderparticles, adhering them to each other and compacting said adheredparticles by a rolling movement.

[0009] The process of the invention comprises feeding powder particlesinto a device suitable for contacting and adhering said particles.According to one embodiment, the process may be started by feedingpowder. In this case, pellet cores are formed from said powderparticles. Powder particles are brought into contact such that some ofthe contacts lead to an adherence of particles to one another. It isusually preferred to use a pharmaceutically acceptable liquid inconjunction with the initial step of forming a pellet from a powder.

[0010] The particles may adhere to each other due to inherent propertiesof the material forming the particles. Powder particles will adhere toone another if they are sufficiently tacky. For some materials, thiswill depend on the temperature. Alternatively, the adherance of thepowder particles may be enhanced by a pharmaceutically acceptableliquid, optionally comprising a binder.

[0011] In accordance with another embodiment, the process is carried outin the presence of preformed pellets, which are designated as cores.Such cores may be homogenous or may have an inner structure. Structuredcores comprise cores made from different materials, arranged forinstance in a layered form, as well as cores having zones of differentdensities. The cores may be prepared by the process of the invention.However, it is also possible to use cores formed by any other technique.

[0012] If the process of the invention is carried out in the presence ofcores, the cores will be coated with a layer which is formed from powderparticles. The cores are brought into contact with powder particlesunder such conditions that will cause the powder particles to adhere tothe surface of the cores. Further powder particles are then contactedwith powder particles which are already adhered to the surface of thecores to form what may be characterized as a further layer of powderparticles, essentially as described above. In this way, a layer frompowder particles surrounding the core is formed.

[0013] According to the invention, during both the formation of coresfrom powder particles and the coating of cores with a layer formed frompowder particles, the particles are being formed into a compacted ordensified layer which is usually more compact or dense than the startingproduct (i.e. has a higher bulk density).

[0014] The process of the present invention may be carried out in arotating device that propels the powder particles onto a tangentiallyarranged surface which causes the powder particles to roll on saidtangentially arranged surface and adhere to other particles thus formingpellets as the particles roll on the tangential surface. The rollingmovement on the tangential surface is believed to result in a compactingforce which is exerted on the adhering particles during the rollingmovement.

[0015] The invention provides a process for making pellets adapted forbiologically active preparations, comprising a core and optionally oneor more layers surrounding said core, wherein said core and/or at leastone of said layers is formed by contacting powder particles, adheringthem to each other and compacting said adhered particles by a rollingmovement, wherein the degree of densification is controlled by theenergy uptake during the rolling movement.

[0016] In order to bring the pellets being formed into a rollingmovement, kinetic energy has to be supplied to them. This can beachieved by moving, e.g. rotating, a moveable, e.g. rotatable, part of asuitable device with which the pellets being formed are in contact.Energy transfer between the moving part of the device and the pelletsbeing formed will be based on frictional forces leading to a rollingmovement of the pellets on surfaces of the device.

[0017] A preferred device comprises a rotor and a chamber wherein saidrotor is located. On rotation of said rotor, the pellets being formedmove in an outward direction on said rotor. Ultimately, the pellets comeinto contact with an inner wall of said chamber which is arranged toreceive the outwardly moving pellets tangentially so that the pelletswill begin to roll as they contact the inner wall of the chamber.

[0018] The preferred device also contains mechanical guide meansarranged above said rotor such that the pellets being formed, afterleaving said rotor, are guided back onto said rotor. Thus, the pelletsbeing formed are put into circulation within the device. This allows thepellets being formed to repeatedly come into contact with powderparticles fed and optionally with a pharmaceutically acceptable liquid.Thereby powder particles may adhere to the pellets being formed so thatthe pellets grow. The adhering powder particles are then subjected to adensification when the pellets undergo a rolling movement, e.g. on oneof the surfaces of the device including the guide means. Because of thecirculation of the pellets being formed in the device the densificationprocess is continuously occurring as the powder is built up on thepellets.

[0019] An especially preferred device for carrying out the process ofthe invention is disclosed in U.S. Pat. No. 6,354,728. The use of thisdevice offers the advantage of a particularly effective rolling movementof pellets in a concussion free manner. In this way, damaging thepellets being formed can be avoided. On the other hand, an effectiveuptake of energy can be achieved.

[0020] In addition to rolling on surfaces of the device in which theprocess is carried out, such as on the rotor surface, the inner wall ofthe chamber and the surface of the mechanical guide means, the rollingmovement also involves rolling interactions within the bed of pelletsbeing formed. These interactions are based on the spin of the pelletsbeing formed. During the rolling movement of the pellets being formed onsurfaces of the device used for carrying out the process, the pelletsacquire a spin. A pellet being formed which rolls on surfaces of thedevice will transfer part of its spin to pellets in direct contact withit. Thus, even pellets which are, during a particular phase of theprocess, not in direct contact with a surface of the device, willperform a rolling movement, more precisely a rolling movement relativeto other pellets, contributing to the densification of the powderparticles.

[0021] Thus, it is preferable to carry out the process in such a mannerthat at least during a part of the processing time an individual pelletbeing formed comes into intimate contact with other pellets beingformed. This requires the quantity of pellets processed in one batch tobe sized to provide a sufficient number of intimate contacts with otherpellets in order to cause the final pellets to have the desiredproperties. Generally, the apparatus that is used in the practice of theinvention should be operated with an initial load of 25 to 100% of thevolume capacity of the rotor. In any event, the apparatus should beoperated with a sufficient load of pellets that individual pellets arecontinuously contacted with other pellets.

[0022] The interactions of the pellets with surfaces of the device andwith each other, as the pellets are formed, results in the applicationof a high shearing 0force on the pellets. It is believed that in thisway, agglomeration of pellets with formation of unwanted lumps isavoided and the pellets formed have a spherical shape and a narrowparticle size distribution.

[0023] Furthermore, it has now surprisingly been found that the degreeof densification of the powder particles fed can be controlled by theenergy uptake during the rolling movement. A larger energy uptake leadsto a higher degree of densification.

[0024] The energy uptake can be measured as the proportion of the energysupplied to the device in which the process is carried out that is usedto supply energy to the pellets being formed. This proportion of theenergy corresponds to the energy supplied which is not consumed by thedevice itself. The energy uptake may be determined by monitoring theconsumption of energy that is required to operate the apparatus. Forexample, the total electrical energy consumed less frictional losses dueto the operation of the empty apparatus may be used to estimate thetotal energy uptake.

[0025] The energy supplied to the pellets being formed, for instance byrotating a rotor in a device containing the pellets, is taken up by thepellets as kinetic energy and as potential energy. This energy taken upis available for the rolling movement of the pellets. During the rollingmovement, energy is used for densification of adhering powder particles.

[0026] If the rotation of a rotor is used to supply kinetic energy tothe pellets being formed, the energy supply can be varied by varying therotor speed. The rotor speed is a process parameter that can be variedto affect the velocity at which the pellets are moved during processing.

[0027] If other factors discussed below are kept constant, a higherrotor speed means a higher energy supply to the pellets being formed.

[0028] The density and the rate at which a biologically active agent isreleased from the pellets may be controlled by modifying the rotor speedwhich has a direct effect on the radial velocity at which the pelletsmove during processing. The rate of release may also be controlled bythe use of other techniques as disclosed herein. The selected rotorspeed will impart a radial velocity to the pellets which has been foundto affect the density of the final pellet. Generally, it has been foundthat rotor speed that impart a radial velocity (measured at the tip ofthe rotor) of about 12-30 meters/second, will in the case of mostbiologically active materials, produce a pellet having a higher densityand a slower release rate of the biologically active material ascompared-to similar pellets made using a lower radial velocity. It hasbeen observed that a rotor speed which induces a radial velocity of from3-10 or more preferably from 4-7.5 meters/second will result in pelletswhich are less dense that the pellets which are produced using a higherradial velocity, i.e. 12-30 meters/second. The pellets containing abiologically active material which are made using a low radial velocitywill generally show a release rate that is more rapid than pellets madewith the same biologically active ingredient and the same excipients atthe same radial velocity.

[0029] When biologically active materials are made into pelletsaccording to the invention by using a high radial velocity, the releaserates are retarded to a greater extent as compared to the release ratesof pellets, made from the same materials, which are made in the sameapparatus using conditions which impart a low radial velocity to thepellets. This effect is very pronounced when water insolublebiologically active materials are utilized in the manufacture ofpellets.

[0030] As disclosed herein, the invention contemplates feeding, aportion of the powder used to make the pellet, in the form of a drypowder as the final or terminal step in the formation of the pellets. Aterminal step of feeding the dry powder may be used to further modifythe release properties of the biologically active material from pelletsprepared according to the invention. As detailed in the examplesprepared below, the pellets produced using a lower radial velocity willhave a slower release rate, of the biologically active material, (from20 to 40% slower at one in the case of ibuprofen) as compared to pelletsmade without the use of dry powder in the terminal step. The use of adry powder feed in a terminal step for pellet formation where thepellets are produced using a high radial velocity is minimal (5-10%slower at one hour in the case of chlorpheniramine.

[0031] Release rates may be determined in a USP 23, Type II dissolutionapparatus using water as a dissolution media. at 37° C. at a stirringspeed of 100 rpm.

[0032] In general, it is believed that pellets made of water insolubledrugs will exhibit the greatest degree of release rate reduction whenmade using high radial velocities in the process of the invention.

[0033] The energy uptake does not only depend on the radial velocity ofthe pellets which is induced by a particular rotor speed, but also onother factors. One such factor is the construction or geometry of thedevice used to carry out the process. If a device such as disclosed inU.S. Pat. No. 6,354,728 is used, the energy uptake can be influenced bythe number of guide vanes contained in the device.

[0034] The energy uptake will also depend on the load of the device,i.e. on the total amount of material contained in the device. The largerthe weight of the material contained in the device, the larger are thecompressive forces exerted on individual pellets due to the weight.

[0035] At a constant rotor speed in the same apparatus, the energyuptake will be higher for a higher load. This has to be taken intoconsideration for the control of the degree of densification since theload of the device will usually vary during the process of theinvention. Making pellets will require feeding of material, such aspowder particles and optionally a pharmaceutically acceptable liquid, sothat the load will increase. If at least during a part of the processingtime, a gas is supplied to remove solvent, this will tend to decreasethe load or reduce the increase if other materials are simultaneouslyfed to the apparatus.

[0036] The energy uptake can further be adjusted by feeding a gas, suchas air under ambient conditions, through the bed of the pellets beingformed. This will be of particular relevance if the process is carriedout at a fairly high loading of the capacity of the apparatus.

[0037] An apparatus suitable for carrying out this embodiment of theprocess of the invention is disclosed in U.S. Pat. No. 6,354,728. Thisdevice comprises a rotor located in a chamber such that an annular gapexists between the rotor and the inner wall of said chamber.Alternatively or in addition, the rotor may contain openings in itssurface allowing a gas to pass through.

[0038] The gas stream, through the openings in the rotor, may bedirected such that forces acting on the pellets being formed are reducedor increased. For instance, a gas may be led through openings in therotor from below to reduce interactions between pellets and the rotorsurface as well as among the pellets. This will reduce the densificationof adhering powder particles. The quantity and flow rate of the gaswhich is passed through the bed of the pellets should not result in asignificant fluidization of the pellet bed.

[0039] The degree of densification of the powder particles will also beinfluenced by the composition of the pellets being formed. One aspect ofthe composition of the pellets being formed is their liquid content. Ahigher liquid content will generally lead to a higher plasticityallowing a more effective densification. However, it has to be notedthat, by the process of the invention, the degree of densification canbe varied for a given composition by regulating the energy uptake of thepellets being formed when these pellets are subjected to a rollingmovement, as described above.

[0040] The degree of densification of the powder particles comprised inthe pellets made by the process of the invention may be determined bythe absolute porosity of the formed pellet or layer. A high porositycorresponds to a low degree of densification, and vice versa.

[0041] The porosity may be visualized by microscopic techniques, forinstance by scanning electron microscopy. Alternatively, the porositymay be determined by mercury intrusion.

[0042] The degree of densification will also be reflected in the densityof the pellets prepared. A higher degree of densification leads to ahigher density. The achieved absolute porosity, i.e. the percentage ofthe total void space with respect to the bulk volume, may vary between0.5 and 30%. Preferably, the absolute porosity has a value of from 1 to20%, more preferably of from 1 to 10%, and especially from 2 to 10%.

[0043] In a preferred embodiment, the invention provides a sphericallyshaped pharmaceutical pellet, comprising a core and optionally at leastone or more layers surrounding said core, wherein said core and/or atleast one of said layers is formed from pellets of a powder adhering toeach other, wherein the degree of densification of said particles has apre-determined value. This profile is expressed in terms of the absoluteporosity of the core and/or at least one of said layers formed frompowder particles and has a va98lue of 0.5 to 30%, preferably 1 to 20%and more preferably 2-10%.

[0044] Preferably, the pellets have at least one layer formed fromparticles of a powder adhering to each other and in certain embodimentsmay have two or more layers adhering to one another.

[0045] The pellets may be made in such a manner that the degree ofdensification is such that a gradient of the degree of densification ina radial direction is achieved or separate concentric zones havingvarying levels of densification may be formed on each pellet, either inthe core or in one or more layers. The degree of densification may becontrolled so that at least one layer has a density that is lower thanthe bulk density of the starting powder.

[0046] Generally the pellets according to the invention will have adiameter of from 0.01 to 5 mm, such as from 0.1 to 2.5 mm. The layer orlayers will each have a layer thickness of from 0.005 to 2.5 mm, such asfrom 0.05 to 1.25 mm. The pellets prepared according to the inventionhave a narrow particle size distribution such that a maximum of 20% byweight of the pellets have a diameter deviating from the averagediameter of all by more than 20%. Preferably, a maximum of 10% by weightof the pellets have a diameter deviating from the average diameter ofall, by more than 20%. Further preferably, a maximum of 20% by weight ofthe pellets have a diameter deviating from the average diameter of allpellets by more than 10% by weight. An especially preferred pelletproduct has a particle size distribution such that a maximum of 10% byweight of the pellets have a diameter deviating from the averagediameter of all pellets by more than 10% by weight. All pervents byweight are based on the total weight of the pellets.

[0047] If desired, the pellets may be made from a core which is notsubstantially spherical.

[0048] A further embodiment of the pellet of the invention may comprisea core for a pharmaceutical dosage form, said core having an inner andan outer zone, said inner zone comprising a biologically active agentand said outer zone comprising a layer which is formed by applying tosaid inner zone, a substantially dry, free flowing inert powder whichforms a non-tacky surface when placed in contact with water. An exampleof a non-tacky surface is the surface of microcrystalline cellulosewhich is wetted with water. The free flowing powder is used to preventthe pellets from sticking to one another or to the apparatus.

[0049] The invention also provides a process for making pharmaceuticalpellets having a core with an inner and an outer zone as describedherein wherein the core or at least one of said layers is formed by (a)contacting powder particles, adhering them to each other and compactingsaid adhered pellets by a rolling movement, wherein the degree ofdensification is controlled by the rolling movement; and (b) feeding asufficient amount of a substantially dry, free flowing inert powderwhich forms a non-tacky surface when placed in contact with water toprovide on said particles an outer zone comprising a layer formed fromsaid substantially dry, free flowing inert powder.

[0050] A preferred embodiment of the invention provides a process ofpreparing pellets by:

[0051] (a) forming a powder mixture which comprises a binder and abiologically active agent;

[0052] (b) feeding said powder mixture which is optionally pre-wettedwith from 0-60wt % of a pharmaceutically acceptable liquid diluent,based on the total weight of the powder mixture and the pharmaceuticallyacceptable diluent, to an operating apparatus which comprises a rotorchamber having an axially extending cylindrical wall, means for passingair through said chamber from the bottom, spray means for feeding aliquid into said chamber, a rotor which rotates on a vertical rotoraxis, said rotor being mounted in said rotor chamber, said rotor havinga central horizontal surface and, in at least the radial outer third ofsaid rotor, the shape of a conical shell with an outward and upwardinclination of between 10° and 80°, said conical shell having acircularly shaped upper edge which lies in a plane which isperpendicular to the rotor axis, feed ports for introducing saidpowdered excipient, a plurality of guide vanes having an outer endaffixed statically to said cylindrical wall of said rotor chamber abovea plane formed by the upper edge of said conical shell of said rotor andan inner end which extends into said rotor chamber and is affixedtangentially to said cylindrical wall of said rotor chamber and having,in cross-section to the rotor axis, essentially the shape of an arc of acircle or a spiral, such that said powdered product which is circulatedby kinetic energy by said rotor under the influence of kinetic energy,moves from said rotor to an inside surface of said guide vanes beforefalling back onto said rotor;

[0053] (c) rotating said rotor, while feeding air and spraying apharmaceutically acceptable liquid into said rotor chamber for asufficient amount of time to form solid pellets having a desireddiameter; and

[0054] (d) feeding a sufficient amount of a substantially dry, freeflowing inert powder which forms a non-tacky surface when placed incontact with water to provide on said pellets an outer zone comprising alayer formed from said substantially dry, free flowing inert powder.

[0055] Accordingly, it is a primary object of the present invention toprovide novel pellets which are useful for the delivery of biologicallyactive agents.

[0056] It is also an object of the invention to provide novel pelletswhich can contain more than 99wt % of an active biological agent, suchas a pharmaceutical.

[0057] It is also an object of the invention to provide particles orpellets which have matrix release characteristics.

[0058] These and other objects of the invention-will become apparentfrom the appended specification.

BRIEF DESCRIPTION OF THE DRAWINGS

[0059]FIG. 1 is a scanning electron microscope (SEM) photograph whichshows a cross-sectional view of a pellet of Example 1.

[0060]FIG. 2 is a scanning electron microscope (SEM) photograph whichshows a cross-sectional view of a pellet of Example 2.

[0061]FIG. 3 is a scanning electron microscope (SEM) photograph whichshows a cross-sectional view of a pellet of Example 3.

[0062]FIG. 4 is a scanning electron microscope (SEM) photograph whichshows a cross-sectional view of a pellet of Example 4.

[0063]FIG. 5 is a photograph of a magnified view of the gross morphologyof the pellets of Example 5.

[0064]FIG. 6 is a scanning electron microscope (SEM) photograph whichshows a cross-sectional view of a pellet of Example 6.

[0065]FIG. 7 is a photograph of a magnified view of the gross morphologyof the pellets of Example 7.

[0066]FIG. 8A is a scanning electron microscope (SEM) photograph of across-sectional view of a pellet of Example 8 made using a low rotorspeed.

[0067]FIG. 8B is a scanning electron microscope (SEM) photograph of across-sectional view of a pellet of Example 8 made using a high rotorspeed.

[0068]FIG. 9 is a scanning electron microscope (SEM) photograph whichshows a cross-sectional view of a pellet of Example 9.

DETAILED DESCRIPTION OF THE INVENTION

[0069] The pellets of the invention are typically prepared using anapparatus which propels particles against a tangentially arranged innerwall in such a manner that a rolling motion is imparted to the movingpellets. A liquid is fed into an apparatus such as the apparatusdisclosed in U.S. Pat. No. 6,449,689 which is adapted to allow for theintroduction of powder during the operation of the apparatus. In oneembodiment of the invention, the process of the invention involves theintroduction of a powder as a final step in the process in order tocontrol and/or terminating pellet growth as well as assisting in thedrying, rounding and smoothing of the pellets. The preferred apparatusis described in U.S. Pat. No. 6,449,869 and U.S. Pat. No. 6,354,728,both of which are incorporated by reference.

[0070] In one embodiment, the pellets of the invention, have an innerzone which has a structure that results from the application of a liquidto a powder in a particle stream under drying conditions. The liquidcauses solid bridges to form and grow until a pellet having a desiredsize is obtained. At that point, the outer zone of the pellet is formedby feeding dry powder to the tumbling bed of pellets in order to causethe pellets to grow to their selected final dimension as well as to dryand smooth the pellets into a highly uniform and highly sphericalproduct.

[0071] When the biologically active material is a pharmaceutical, it maybe any physiologically or pharmacologically active substance thatproduces a local or systemic effect, in animals, including warm-bloodedmammals, humans and primates

[0072] The pharmaceutically acceptable liquid which is used in theformation of the pellets may comprise one or more components selectedfrom the group consisting of biologically active ingredients, binders,diluents, disintegrants, lubricants, flavoring agents, coloring agents,surfactants, anti-sticking agents, osmotic agents, matrix formingpolymers, film forming polymers, release controlling agents and mixturesthereof, in dissolved, suspended or dispersed form. Generally, onlyselected components will be employed to achieve the desired result for agiven formulation. The particular formulation will determine if, whenand how the listed components are added.

[0073] The process of the invention also includes the introduction, of apowder into a moving stream of partially formed pellets, as a means ofcontrolling the growth of the pellets as well as assisting in therounding and smoothing of the pellets.

[0074] The active pharmaceutical that can be delivered includesinorganic and organic compounds without limitation, including drugs thatact on the peripheral nerves, adrenergic receptors, cholinergicreceptors, nervous system, skeletal muscles, cardiovascular system,smooth muscles, blood circulatory system, synaptic sites, neuroeffectorjunctional sites, endocrine system, hormone systems, immunologicalsystem, reproductive system, skeletal system, autacoid systems,alimentary and excretory systems, inhibitory of autocoid systems,alimentary and excretory systems, inhibitory of autocoids and histaminesystems. The active drug that can be delivered for acting on theserecipients include anticonvulsants, analgesics, anti-inflammatories,calcium antagonists, anesthetics, antimicrobials, antimalarials,antiparasitic, antihypertensives, antihistamines, antipyretics,alpha-adrenergic agonist, alpha-blockers, biocides, bactericides,bronchial dilators, beta-adrenergic blocking drugs, contraceptives,cardiovascular drugs, calcium channel inhibitors, depressants,diagnostics, diuretics, electrolytes, hypnotics, hormonals,hyperglycemics, muscle contractants, muscle relaxants, ophthalmics,psychic energizers, parasympathomimetics, sedatives, sympathomimetics,tranquilizers, urinary tract drugs, vaginal drugs, vitamins,nonsteroidal anti-inflammatory drugs, angiotensin converting enzymes,polypeptide drugs, and the like.

[0075] Exemplary drugs that are very soluble in water and can bedelivered by the pellets of this invention include prochlorperazine,ferrous sulfate, aminocaproic acid, potassium chloride, mecamylaminehydrochloride, procainamide hydrochloride, amphetamine sulfate,amphetamine hydrochloride, isoproteronol sulfate, methamphetaminehydrochloride, phenmetrazine hydrochloride, bethanechol chloride,methacholine chloride, pilocarpine hydrochloride, atropine sulfate,scopolamine bromide, isopropamide iodide, tridihexethyl chloride,phenformin hydrochloride, methylphenidate hydrochloride, cimetidinehydrochloride, theophylline cholinate, cephalexin hydrochloride,oxybutynin hydrochloride and the like.

[0076] Exemplary drugs that are poorly soluble in water and that can bedelivered by the particles of this invention include diphenidol,meclizine hydrochloride, omeprazole prochlorperazine maleate,phenoxybenzamine, thiethylperzine maleate, anisindone, diphenadione,erythrityl tetranitrate, digoxin, isoflurophate, acetazolamide,methazolamide, bendro-flumethiazide, chlorpropamide, tolazamide,chlormadinone acetate, phenaglycodol, allopurinol, aluminum aspirin,methotrexate, acetyl sulfisoxazole, erythromycin, progestins,progestational, corticosteroids, hydrocortisone hydrocorticosteroneacetate, cortisone acetate, triamcinolone, methyltestosterone, 17beta-estradiol, ethinyl estradiol, ethinyl estradiol 3-methyl ether,prednisolone, 17 betahydroxyprogesterone acetate, 19 non-progesterone,norgesterel, norethindrone, norethisterone, norethiederone,progesterone, norgesterone, norethynodrel, and the like.

[0077] Examples of other drugs that can be formulated according to thepresent invention include aspirin, indomethacin, naproxen, fenoprofen,sulindac, indoprofen, nitroglycerin, isosorbide dinitrate, timolol,atenolol, alprenolol, cimetidine, clonidine, imipramine, levodopa,chloropromazine, methyldopa, dihydroxyphenylalamine, pivaloyloxyethylester of alpha-methyldopa hydrochloride, theophylline, calciumgluconate, ketoprofen, ibuprofen, cephalexin, erythromycin, haloperidol,zomepirac, ferrous lactate, vincamine, diazepam, phenoxybenzamine,diltiazem, milrinone, captopril, madol, propranolol hydrochloride,quanbenz, hydrochlorothiazide, ranitidine, flurbiprofen, fenbufen,fluprofen, tolmetin, alolofenac, mefanamic, flufenamic, difuninal,nimodipine, nitrendipine, nisoldipine, nicardipine, felodipine,lidoflazine, tiapamil, gallopamil, amlodipine, mioflazine, lisinolpril,enalapril, captopril, ramipril, endlapriate, famotidine, nizatidine,sucralfate, etintidine, tertatolol, minoxidil, chlordiazepoxide,chlordiazepoxide hydrochloride, diazepam, amitriptylin hydrochloride,impramine hydrochloride, imipramine pamoate, enitabas, buproprion, andthe like.

[0078] Other examples of biologically active materials include watersoluble vitamins such as the B Vitamins, Vitamin C and the oil solublevitamins such as Vitamin A, D, E and K. Neutraceuticals such aschondroitin, glucosamine, St. John's wort, saw palmetto and the like mayalso be formed into pellets according to the present invention.

[0079] In the case of pellets having an inner and an outer zone, theinner zone of the pellets may comprise, depending on the properties ofthe biological agent, from 0.1-99wt % or from 3 to 90wt % or from 5 to60wt % of a biologically active agent, based on the total weight of thepellet of one or more pharmaceutically acceptable binders and/ordiluents based on the weight of the pellet. Suitable binders for use inthe invention include those materials that impart cohesive properties tothe powdered biologically active material when admixed dry or in thepresence of a suitable solvent or liquid diluent. These materialscommonly include starches such as pregelatinized starch, gelatin, andsugars such as sucrose, glucose, dextrose, molasses and lactose. Naturaland synthetic gums include acacia, sodium alginate, extract of Irishmoss, panwar gum, ghatti gum, mucilage of isapol husks, carboxymethylcellulose, methylcellulose, microcrystalline cellulose,polyvinylpyrrolidone e.g. povidone U.S.P K30, Veegum, and larcharabogalactan. Binders are used in an effective amount, e.g. 1 to 10wt%, based on the total weight of liquid and binder to cause a sufficientdegree of agglomeration of the powders that stable particles are rapidlyformed.

[0080] An outer zone may be formed by applying to the inner zone, apowder which comprises a substantially dry, free flowing inert powderwhich forms a non-tacky surface when placed in contact with water.Examples of such free flowing inert powders include water soluble andwater insoluble materials. Examples of useful materials includemicrocrystalline cellulose, dicalcium phosphate, calcium sulfate, talc,an alkali metal stearate, silicon dioxide and calcium carbonate.

[0081] The powder which comprises a substantially dry, free flowinginert powder, may also include an active biological agent. For example,a particle having an outer zone formed from a substantially dry, freeflowing inert powder and a biological agent, may contain, depending onthe properties of the biological agent, from 0.1-99wt % or from 3 to90wt % or from 5 to 60wt % of a biologically active agent, based on thetotal weight of the pellet. In certain cases, it may be convenient toset aside from 5 to 35wt %, preferably 10 to 25wt % based on the weightof the total amount of the biological agent and the binder, prior tofeeding the initial charge of binder and biological agent to theapparatus. The powder which is set aside may be used to form the outerzone of the pellets in the last stage of the process. This will resultin the pellet having a homogeneous formulation but will still result inthe formation of inner and outer zones having different densities.

[0082] Other additives that may be used in the pellet of the inventioninclude diluents, lubricants, disintegrants, coloring agents and/orflavoring agents. The pellets may have a homogeneous or a heterogeneouscore. The homogenous core may be made from one or more biologicallyactive agents which may be homogeneously blended or may be applied asdiscrete layers. Heterogeneous cores will comprise a base which may bean inorganic or organic substrate to which concentric layers are appliedusing the process of the invention as described herein. The substratemay comprise an inorganic salt such as calcium phosphate or a non-pareilsugar-starch sphere or a microcrystalline cellulose seed.

[0083] In the case of a homogeneous or a heterogeneous core, a pluralityof layers of biologically active materials, inert materials, or releasecontrolling layers may be applied depending on the desired biologicaleffect.

[0084] The pellets according to the invention may be made by using anapparatus that is described in U.S. Pat. No. 6,354,728. That apparatuscomprises a rotor chamber having an axially extending cylindrical wall,means for passing air through said chamber from the bottom, spray meansfor feeding a liquid into said chamber, a rotor which rotates on avertical rotor axis, said rotor being mounted in said rotor chamber,said rotor having a central horizontal surface and, in at least theradial outer third of said rotor, the shape of a conical shell with anoutward and upward inclination of between 10° and 80°, said conicalshell having a circularly shaped upper edge which lies in a plane whichis perpendicular to the rotor axis, feed ports for introducing saidpowdered excipient, a plurality of guide vanes having an outer endaffixed statically to said cylindrical wall of said rotor chamber abovea plane formed by the upper edge of said conical shell of said rotor andan inner end which extends into said rotor chamber and is affixedtangentially to said cylindrical wall of said rotor chamber and having,in cross-section to the rotor axis, essentially the shape of an arc of acircle or a spiral, such that said powdered product which is circulatedby kinetic energy by said rotor under the influence of kinetic energy,moves from said rotor to an inside surface of said guide vanes before itfalls back onto said rotor.

[0085] When the desired pellet size is substantially achieved, it ispreferred to feed dry powder to the apparatus and the apparatus isallowed to run for a period of 3 to 15 minutes, and preferably 5 to 10minutes to complete the formation of the pellets.

[0086] It is also contemplated that some additional drying at atemperature of from about 30 to 100° C., and preferably from about 40 to90° C. until the moisture content is from 1 to 10wt %, based on thetotal weight of the pellets depending on the particular biologicallyactive material and/or the particular excipients. Drying may be carriedout in the preferred apparatus of the invention for making the pelletsor in a separate dryer such as a fluid bed dryer.

[0087] The process is preferably based on the use of a minimal amount ofliquid in order to avoid causing substantial swelling or gelation of anymatrix forming materials which are placed on the pellet according to theinvention.

[0088] The matrix forming material may be any swellable or non-swellablematerial that provides in vitro dissolution rates of a biologicallyactive agent within the narrow ranges required to provide the desiredplasma level of the biologically active agent over a desired intervalwhich is typically 12 to 24 hours. Most matrix forming material willalso provide for the release of the biologically active agent in a pHindependent manner. Preferably the matrix is a controlled releasematrix, although normal release matrices having a coating that controlsthe release of the drug may be used. Suitable water-swellable materialsfor inclusion in a controlled release matrix are

[0089] (a) Hydrophilic polymers, such as gums, cellulose ethers, acrylicresins and protein derived materials. Of these polymers, the celluloseethers, especially hydroxyalkylcelluloses and carboxyalkylcelluloses,are preferred. The pellets may contain between 1% and 35wt % of ahydrophilic or hydrophobic polymer.

[0090] (b) Digestible, long chain (C₈-C₅₀, especially C₁₂-C₄₀),substituted or unsubstituted hydrocarbons, such as fatty acids, fattyalcohols, glyceryl esters of fatty acids, mineral and vegetable oils andwaxes. Hydrocarbons having a melting point of between 25° and 90° C. arepreferred. Of these long chain hydrocarbon materials, fatty (aliphatic)alcohols are preferred. The pellets may contain up to 60% (by weight) ofat least one digestible, long chain hydrocarbon.

[0091] c) Polyalkylene glycols. The pellets may contain up to 60% (byweight) of at least one polyalkylene glycol.

[0092] One particular suitable matrix forming material comprises a watersoluble hydroxyalkyl cellulose, at least one C₁₂-C₃₆, preferablyC₁₄-C₂₂, aliphatic alcohol and, optionally, at least one polyalkyleneglycol.

[0093] The hydroxyalkyl cellulose is preferably a hydroxy (C₁ to C₆)alkyl cellulose, such as hydroxypropylcellulose (HPC) or hydroxypropylmethylcellulose (HPMC). The nominal viscosity of the HPC or HPMC may bebetween 2,500 and 100,000 (2%w/v sol. at 20° C.) and preferably 5,000 to50,000. The amount of the matrix forming material in the pellet will bedetermined, inter alia, by the precise rate of release required. Thismay be done by using conventional release rate testing procedures suchas those described in U.S.P. 23, which testing procedures areincorporated by reference. When the pellets are formulated to contain amatrix polymer, the pellets will contain between 1% and 40wt. %,especially between 5% and 20 wt. % of HPC or HPMC, based on the totalweight of the pellets.

[0094] When forming pellets with water-swellable matrix formingmaterials, care should be exercised to prevent the matrix formingmaterials from swelling due to prolonged contact with liquid diluents inorder to prevent the water-swellable matrix forming material fromforming a gel during the pellet formation step.

[0095] Non-swellable matrix forming materials comprise water insoluble,dispersible polymers include the commercially availableacrylic/methacrylic polymers as well as ethyl cellulose. Theacrylic/methacrylic polymers are available under various tradenames suchas Eudragit. These materials are used as non-swellable matrix formingpolymers when they are admixed with biologically active compounds andvarious excipients which are formed into pellets according to thepresent invention. Generally from 1 to 30wt %, of non-swellable matrixforming polymer, based on the weight of biologically active agent,excipient and non-swellable matrix forming polymer of may be admixed forthe purpose of making a powder which may be formed into pelletsaccording to the invention.

[0096] A release rate controlling polymer membrane may be applied to thepellets to provide for sustained release, delayed release, e.g. releasein the small intestine by using a pH sensitive coating such as anenteric coating. Suitable enteric coatings include polymeric entericcoating material. The enteric coatings are “pH dependent” whichdescribes the well known effect of an enteric coating which preventsrelease of the dosage form in the low pH conditions of the stomach butpermits release in the higher pH conditions of the small intestine. Theenteric coating will comprise from 1 to 25wt % and preferably from 5 to10wt % of the total weight of the pellets. The enteric coating polymermay be selected from the group consisting of shellac, methacrylic acidcopolymers, (Eudragit S or L) cellulose acetate phthalate,hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcelluloseacetate succinate, cellulose acetate trimellitate and polyvinyl acetatephthalate. Methacrylic acid copolymer, Type B USP/NFXXII which dissolvesat a pH above about 6.0 is preferred. The thickness of the coating isselected to provide the desired release rate depending on the thicknessof the coating and the particular coating.

[0097] A commercially available copolymer is Eudragit S100 which isbased on methacrylic acid and methyl methacrylate and has a weightaverage molecular weight of about 150,000. Other auxiliary coating aidssuch as a minor amount (1-5wt % based on the active core component andthe total weight of the final coating) of a plasticizer such asacetyltributyl citrate, triacetin, acetylated monoglyceride, rape oil,olive oil, sesame oil, acetyltriethylcitrate, glycerin sorbitol,diethyloxalate, diethylmalate, diethylfumarate, dibutylsuccinate,diethylmalonate, dioctylphthalate, dibutylsebacate, triethylcitrate,tributylcitrate, glyceroltributyrate, polyethyleneglycol (molecularweight of from 380 to 420), propylene glycol and mixtures thereof incombination with an antisticking agent which may be a silicate such astalc. An antisticking agent, such as talc may be added in an amountwhich is effective to prevent sticking of the pellets. These componentsmay be added to the methacrylic acid copolymer in combination withappropriate solvents.

[0098] A sustained release coated pellet may be coated with a polymericmaterial which will substantially maintain its integrity in the varyingpH conditions of the gastrointestinal tract but is permeable to theparticular biologically active agent which is being formulated. Thesustained release coating is used at a level that is selected to releasethe biologically active agent at a rate that will provide the desired invivo release characteristics that will provide the desired plasmaprofile for the selected biologically active agent. Polymers such asethyl cellulose, cellulose acetate, cellulose acetate butyrate, or anacrylic. copolymer which when used in a sufficient amount will cause thecoated pellet to release the biologically active agent after ingestionof the dosage form of the invention. Materials such as Eudragit RS 30D;RS 100; NE 30D; RL 30D or RL 100 may be used to prepare the delayedpulse pellet. One such useful material is an acrylate copolymer whichhas a permeability which is independent of pH. That acrylate copolymeris commercially available as Eudragit RS30D which is available as a 30wt% aqueous dispersion of copolymers of acrylic and methacrylic acidesters, having a number average molecular weight of 150,000 with a lowcontent of quaternary ammonium groups. Other auxiliary coating aids suchas a minor amount (3-7wt % based on the total weight of the active corecomponent and the total weight of the final coating) of a plasticizersuch as acetyltributyl citrate, triacetin, acetylated monoglyceride,rape oil, olive oil, sesame oil, cetyltriethylcitrate, glycerinsorbitol, diethyloxalate, diethylmalate, diethylfumarate,dibutylsuccinate, diethylmalonate, dioctylphthalate, dibutylsebacate,triethylcitrate, tributylcitrate, glyceroltributyrate,polyethyleneglycol (molecular weight of from 380 to 420), propyleneglycol and mixtures thereof.

[0099] If a disintegrant is employed, it may comprise from 2 to 8wt. %based on the total weight of the pellet, of starch, clay, celluloses,algins, gums and cross-linked polymers. Super disintegrants such ascross-linked cellulose, cross-linked polyvinylpyrrolidone,Croscarmellose sodium, carboxymethylcellulose and the like may also beemployed if it desired to have a rapid release of the biologicallyactive agent.

[0100] Conventional osmotic agents include non-toxic inorganic saltssuch as sodium chloride, potassium chloride, disodium phosphate and thelike or water soluble non-toxic organic compounds such as lactose,sucrose, dextrose and the like. Antisticking agents such as talc may beemployed to achieve any required result.

[0101] The pellets of the invention may be placed in hard or softgelatin capsules to prepare finished dosage forms suitable foradministration to a patient or they may be used to prepare compressedtablets using suitable cushioning agents, diluents, binders,disintegrants and lubricants.

DESCRIPTION OF THE PREFERRED EMBODIMENTS EXAMPLE 1

[0102] Chlorpheniramine maleate pellets (10% concentration), wereproduced at low rotor speed (300 rpm) which induces a radial velocity ofabout 4.7 meters/second in the pellets as compared to pellets producedat high rotor speed (1000 rpm) which induces a radial velocity of aboutmeters/second in an apparatus described in U.S. Pat. No. 6,354,728.

[0103] Process conditions: Low rotor speed: Formulation:Chlorpheniramine maleate (CPM) 100 g Microcrystalline cellulose (grade101) 900 g

[0104] 1. Blend CPM and MCC in a plastic bag.

[0105] 2. Prewet CPM/MCC blend with 300 g water in a VG (vertical highshear granulator).

[0106] 3. Transfer prewetted blend into an apparatus made according toU.S. Pat. No. 6,354,728.

[0107] 4. Set the apparatus controls as follow:

[0108] Spray rate 35 g/min

[0109] Four baffles (shallow)

[0110] Atomization air pressure 30%

[0111] Rotor speed (low) 300 rpm

[0112] 5. Spray—700-1000 g of water

[0113] 6. Finish spraying water.

[0114] 7. Discharge the wet pellets. Dry in a GPCG-1 (granulator dryer)at a temperature of 80° C. to a moisture content of <3%

[0115]FIG. 1 is an SEM of a cross-sectional view of the pellet producedin Example 1.

[0116] Analytical Testing:

[0117] Dissolution of chlorpheniramine maleate from pellets (841-1190micron), using USP dissolution testing at 60 min time point 98.2%

[0118] Bulk density of pellets (841-1190 micron) 0.67 g/cc

EXAMPLE 2

[0119] Formulation: Chlorpheniramine maleate (CPM) 100 g MCC (grade 101)900 g

[0120] 1. Blend CPM and MCC in a plastic bag.

[0121] 2. Prewet CPM/MCC blend with 300 g water in a VG.

[0122] 3. Transfer prewetted blend into the apparatus used in Example 1.

[0123]4. Set the parameter for the apparatus as follow: spray rate 35g/min. Four baffles (shallow) Atomization air pressure 30% Rotor speed(high) 1000 rpm

[0124] 5. Spray˜700-1000 g of water.

[0125] 6. Finish spraying water.

[0126] 7. Discharge the wet pellets. Dry in a CPCG-1 at a temperature of80° C. to a moisture content of <3%.

[0127]FIG. 2 is an SEM which shows a cross-sectional view of the pelletproduced in Example 2.

[0128] Analytical Testing:

[0129] Dissolution of chlorpheniramine maleate from pellets (841-1190micron), using USP dissolution testing at 60 min time point 89.5%

[0130] Bulk density of pellets (841-1190 micron) 0.80 g/cc

[0131] Pellets produced using low rotor speed (Example 1) and high rotorspeed (Example 2) have different physical characteristics (pellet shape,bulk density, pellet structure).

[0132] The pellets produced using high rotor speed at the statedconditions are irregular in shape (not spherical). These pellets may beused as an intermediate in the preparation of spherical pellets.

[0133] Drug release of pellets produced using low rotor speed and highrotor speed also differ. Chlorpheniramine maleate pellets that wereproduced using low rotor speed (Example 1) have lower bulk density (0.67vs. 0.80 g/cc) and higher drug release at 60 min time point (98.2 vs.89.5%) when compared to the pellets produced using high rotor speed(Example 2).

EXAMPLE 3

[0134] Formulation: Chlorpheniramine maleate (CPM) 100 g MCC (grade 101)900 g

[0135] 1. Blend CPM and MCC in a plastic bag.

[0136] 2. Prewet CPM/MCC blend with 300 g water in a VG.

[0137] 3. Transfer prewetted blend into the apparatus of Example 1.

[0138] 4. Set the parameter for processing as follows: Spray rate 35g/min Four baffles (shallow) Atomization air pressure 30% Rotor speed(low) 300 rpm

[0139] 5. After 600 g water sprayed, change the rotor speed to 1000 rpm,continue spraying water. Additional amount of water to spray˜200-400 g.

[0140] 6. Finish spraying water.

[0141] 7. Discharge the wet pellets. Dry in a GPCG-1 to moisture of <3%

[0142]FIG. 3 is an SEM which shows a cross-sectional view of the pelletproduced in Example 3.

[0143] Analytical testing:

[0144] Dissolution of chlorpheniramine maleate from pellets (841-1190micron), using USP dissolution testing at 60 min time point 90.4%

[0145] Bulk density of pellets (841-1190 micron) 0.79 g/cc

[0146] Summary:

[0147] The pellets produced using low speed initially and adjusting tohigh rotor speed during processing (Example 3) have higher bulk density(0.79 vs. 0.67 g/cc) and lower drug release (90.4 vs. 98.2%) whencompared to pellets produced using low rotor speed (Example 1). Surfacemorphology of the pellets produced using low speed initially andadjusting to high rotor speed during processing (Example 3) was alsosmoother than the surface the pellets produced using low rotor speed(Example 1).

[0148] Summary: Effect of Rotor Speed TABLE 1 Effect of Rotor Speed onBulk Density and Drug Release of Chlorpheniramine maleate Pellets (10%concentration) Low High Low/High Rotor speed (Ex 1) (Ex 2) (Ex 3) Bulkdens. 0.67 g/cc 0.80 g/cc 0.79 g/cc Drug rel. 98.2% 89.5% 90.4% (60 mintimepoint)

EXAMPLE 4

[0149] To demonstrate the effect of the powder feeding step, 20% oftotal weight of blend was set aside to powder feed at the end ofspraying process, process is described below. The pellets are comparedto the pellets produced at the same low or high rotor speed, describedin Example 1 and Example 2. Formulation: Chlorpheniramine maleate (CPM)100 g MCC (grade 101) 900 g

[0150] 1. Blend CPM and MCC in a plastic bag. Weigh 200 g for powderfeeding.

[0151] 2. Prewet CPM/MCC blend with 250 g water in a VG.

[0152] 3. Transfer prewetted blend into the apparatus of Example 1.

[0153] 4. Set the parameter for processing as follows: Spray rate 35g/min

[0154] Four baffles (shallow)

[0155] Atomization air pressure 30%

[0156] Rotor speed (low) 300 rpm

[0157] 5. Spray˜700-1000 g of water

[0158] 6. Start powder feed at powder feed rate of 40 g/min. Reducespray rate to 20 g/min and continue spraying water.

[0159] 7. Finish spraying water, finish powder feed.

[0160] 8. Discharge the wet pellets. Dry in a CPCG-1 to moisture of <3%

[0161]FIG. 4 is an SEM photograph which shows a cross-sectional view ofa pellet made by the procedure of Example 4.

[0162] Analytical Testing:

[0163] Dissolution of chlorpheniramine maleate from pellets (841-1190micron), using USP dissolution testing at 60 min time point 101.9%

[0164] Bulk density of pellets (841-1190 micron) 0.76 g/cc

EXAMPLE 5

[0165] High rotor speed with powder feeding step Formulation:Chlorpheniramine maleate (CPM) 100 g MCC (grade 101) 900 g

[0166] 1. Blend CPM and MCC in a plastic bag. Weigh 200 g for powderfeeding.

[0167] 2. Prewet CPM/MCC blend with 250 g water in a VG.

[0168] 3. Transfer prewetted blend into the apparatus of Example 1.

[0169]4. Set the parameter for processing as follows: Spray rate 35g/min. Four baffles (shallow) Atomization air pressure 30% Rotor speed(high) 1000 rpm

[0170] 5. Spray˜700-1000 g of water.

[0171] 6. Start powder feed at powder feed rate of ˜40 g/min. Reducespray rate to 20 g/min and continue spraying water.

[0172] 7. Finish spraying water, finish powder feed.

[0173] 8. Discharge the wet pellets. Dry in a CPCG-1 to moisture of <3%.

[0174]FIG. 5 shows the gross morphology of pellets made by the procedureof Example 5.

[0175] Analytical testing;

[0176] Dissolution of chlorpheniramine maleate from pellets (841-1190micron), using USP 23 dissolution apparatus with water at 60 minute timepoint 84.7%

[0177] Bulk density of pellets (841-1190 micron) 0.79 g/cc

[0178] Summary:

[0179] The processes without powder feeding step (Example 1 for lowrotor speed and Example 2 for high rotor speed) were compared to theprocesses with powder feeding step (Example 4 for low rotor speed andExample 5 for high rotor speed). Other process parameters were keptconstant so that the only variable during the two processes is powderfeeding step.

[0180] Powder feeding step at the end of spraying process improvedpellets shape and surface morphology of pellets for both low and highrotor speed condition (comparing Example 4 to Example 1 and Example 5 toExample 2). The effect of powder feeding on pellet shape was morepronounced at high rotor speed condition (significantly more sphericalwith powder feeding step—Example 4 compared to Example 2). The surfacemorphology was smoother for the pellet produced using powder feedingstep (Example 4 compared to Example 1.).

[0181] Chlorpheniramine release from the pellets was not significantlyaffected by powder feeding step at low rotor speed condition (98.2%without powder feeding step vs. 101.9% with powder feeding step). Athigh rotor speed condition, pellets produced using powder feeding stephas slightly lower drug release at 60 min time point (84.7% vs. 89.5%without powder feeding step).

EXAMPLE 6

[0182] 1.8 kg. of pellets (av. diameter 710-850 microns) that were madefrom microcrystalline cellulose (101) were placed in an apparatusaccording to U.S. Pat. No. 6,354,728. The rotary atomizer was used tospray into the apparatus a solution of chlorpheniramine maleate (CPM)(0.2 kg dissolved in 0.2 kg. of water at a rate of about 19 g/min. whichwas increased to a rate of about 30 g/min. The radial velocity was 8.9meters/second. After the CPM solution spraying is complete, the processwas continued in the same apparatus by introducing a water spray atabout 30 g/min. and a powder blend of 0.8 kg of carboxypolymethylene(Carbopol 971P) and 0.2 kg of talc (S500) at a rate of approximately30-50 g/min. The water spray rate is increased to about 38 g/min. Thepellets begin to stick to one another and the powder feed and waterspray are stopped and about 230 g of microcrystalline cellulose powder(MCC) is added to the apparatus. Spraying is restarted at a rate ofabout 38 g/min. and the powder blend is fed intermittently withadditional 230 g portions of MCC. The water spray rate is decreased toabout 9 g/min. and all, of the powder blend is fed to the apparatus.

[0183] An additional 270 g portion of MCC is fed with a water spray at arate of about 37 g/min. and the powder is fed at a rate of about 30-50g/min. After the powder feed is complete, the process is terminated andthe pellets are dried in a GPCG-1 fluid bed drier at about 80° C. untilthe pellets are dried to about a 5wt % average moisture content based onthe total weight of the pellets.

[0184] The average diameter of the pellets was approximately 800microns.

[0185] The pellets were tested to determine the rate at which the CPMwas released in a USP 23 Type II apparatus at 37° C. at a paddle speedof 100 rpm in water. The results were as follows: Time % CPM released0.5 h 26.3   1 hr 29.8   2 hr 34.0   3 hr 44.2   6 hr 55.0   8 hr 59.9 12 hr 61.1

[0186]FIG. 6 is an SEM photograph which shows a cross-section of apellet made by the procedure of Example 6.

EXAMPLE 7

[0187] Pellets were made according to the following procedure: Ibuprofen25 (BASF) 3,600 g Polyvinylpyrrolidone (PVP K-30))   200 g MCC (Vivapor101)   200 g

[0188] The blend was mixed in a VG for 1.5 min. A 1.5 kg portion wassegregated for later use as a powder feed during the last step of theprocess. Then 2.5 kg of the blended powders were then loaded into anapparatus that is described in U.S. Pat. No. 6,354,728.

[0189] Spraying was initiated with water containing 0.1w % of Tween 80.The spray rate was 19 g/min. and the initial rotor speed was 475 rpm(8.9 meters/sec.) (70%) gradually increasing to 550 rpm (10.4meters/sec. (80%). After 320 g was sprayed, the spray rate was increasedto about 40 g/min.which seemed to be too fast. The spray rate was thenreduced to about 29 g/min. When 750 g had been sprayed, it appeared thatsome powder had been sucked in through the powder feed port. After 863 ghad been sprayed, the spray rate was increased to about 40 g/min. andpowder feeding was started at a rate of about 66 g/min. The liquid sprayrate was decreased to about 29 g/min. Spraying was stopped after 1379 ghad been sprayed and all of the powder (1.25 kg) was added and the rotorwas operated for about 4 minutes after the powder feeding was complete.The total process time was about 50 min. The pellets were dried in aGPCG-1 at 55-65° C. until the product temperature was 45° C. The grossmorphology of the pellets is shown in FIG. 7. The average size isapproximately 800 microns.

EXAMPLE 8

[0190] Ibuprofen pellets (10% concentration) that are produced at lowrotor speed (300 rpm) are compared to pellets produced at high rotorspeed (1000 rpm).

[0191] II Ibuprofen (IBU) 100 g MCC (grade101) 900 g

[0192] 1. Blend IBU and MCC in a plastic bag.

[0193] 2. Prewet IBU/MCC blend with 300 g water in a VG.

[0194] 3. Transfer prewetted blend into the apparatus of Example 1.

[0195] 4. Set the parameter for processing as follows: Spray rate 35g/min

[0196] i. Four baffles (shallow)

[0197] ii. Atomization air pressure 30%

[0198] iii. Rotor speed (low) 300 rpm

[0199] 5. Spray˜700-1000 g of water

[0200] 6. Finish spraying water.

[0201] 7. Discharge the wet pellets. Dry in a GPCG-1 to moisture of <5%

[0202] Analytical Testing:

[0203] Dissolution of Ibuprofen from pellets (841-1190 micron), usingUSP dissolution testing at 60 min time point 72.1% Bulk density ofpellets (841-1190 micron) 0.66 g/cc

[0204] Process conditions: High rotor speed Formulation: Ibuprofen (IBU)100 g MCC (grade101) 900 g

[0205] 1. Blend IBU and MCC in a plastic bag.

[0206] 2. Prewet IBU/MCC blend with 300 g water in a VG.

[0207] 3. Transfer prewetted blend into the apparatus of Example 1. Setthe parameter for processing as follows: Spray rate 35 g/min.

[0208] Four baffles (shallow)

[0209] Atomization air pressure 30%

[0210] Rotor speed (high) 1000 rpm

[0211] 4. Spray˜700-1000 g of water.

[0212] 5. Finish spraying water.

[0213] 6. Discharge the wet pellets. Dry in a GPCG-1 to moisture of <5%.

[0214] Analytical Testing:

[0215] Dissolution of Ibuprofen from pellets (841-1190 micron), usingUSP dissolution testing at 60 min time point 38.6% Bulk density ofpellets (841-1190 micron) 0.80 g/cc

[0216]FIG. 8A is a SEM of a cross-section of a pellet made using a lowrotor speed and FIG. 8B is a SEM of a cross-section of a pellet made athigh rotor speed.

[0217] Summary:

[0218] Ibuprofen pellets produced using low rotor speed and high rotorspeed have different physical characteristics (particle shape, bulkdensity, pellet structure). The pellets produced using high rotor speedare not as spherical as the pellets produced using low rotor speed.

[0219] Drug release of pellets produced using low rotor speed and highrotor speed also differs. Ibuprofen, which is a water insolublecompound, released at significantly slower rate from pellets produced athigh rotor speed than from pellets produced at low rotor speed (38.6%vs. 72.1%). The bulk density of pellets produced at high rotor speed washigher than that of pellets produced at low rotor speed (0.80 vs. 0.66g/cc) . Pellet structure (under scanning electron microscope) was denserfor pellets produced at high rotor speed.

EXAMPLE 9

[0220] Pellets were made using a combination of low and high rotorspeeds as follows: Formulation: Ibuprofen (IBU) 100 g MCC (grade101) 900g

[0221] 1. Blend IBU and MCC in a plastic bag.

[0222] 2. Prewet IBU/MCC blend with 300 g water in a VG.

[0223] 3. Transfer prewetted blend into the apparatus of Example 1.

[0224] 4. Set the parameter for the apparatus of Example 1 processing asfollows:

[0225] 5. Spray rate 35 g/min

[0226] Four baffles (shallow)

[0227] Atomization air pressure 30%

[0228] Rotor speed (low) 300 rpm

[0229] 6. After 600 g water sprayed, change the rotor speed to 1000 rpm,continue spraying water. Additional amount of water to spray˜200-400 g.

[0230] 7. Finish spraying water.

[0231] 8. Discharge the wet pellets. Dry in a GPCG-1 to moisture of <5%

[0232] Analytical Testing:

[0233] Dissolution of Ibuprofen from pellets (841-1190 micron), usingUSP dissolution testing at 60 min time point 60.2%% Bulk density ofpellets (841-1190 micron) 0.75 g/cc

[0234]FIG. 9 is an SEM of a cross-section of a pellet made according toExample 9.

[0235] Summary:

[0236] The Ibuprofen pellets produced using low speed initially andadjusting to high rotor speed during processing (Example 9) have higherbulk density (0.75 vs. 0.66 g/cc) and lower drug release (60.2% vs.72.1%) when compared to pellets produced using low rotor speed (Example8). Surface morphology of the pellets produced using low speed initiallyand adjusting to high rotor speed during processing was slightlysmoother than the surface the pellets produced using low rotor speed

[0237] Summary: Effect of Rotor Speed

[0238] Table II.1: Effect of Rotor Speed on Bulk Density and DrugRelease of Ibuprofen Pellets (10% concentration) Rotor Speed Low rotorspeed initially, adjusted to high rotor Low rotor High Rotor speedduring speed Speed processing (Ex. 8) (Ex. 8) (Ex. 9) Bulk density 0.66g/cc 0.80 g/cc 0.75 g/cc Drug release 72.1% 38.6% 60.2% (60 mintimepoint)

EXAMPLE 10

[0239] To investigate the effect of powder feeding step, 20% of totalweight of blend was set aside to powder feed at the end of sprayingprocess, process is described below. The pellets are compared to thepellets produced at the same low or high rotor speed, described inExample 8. Formulation: Ibuprofen (IBU) 100 g MCC (grade101) 900 g

[0240] 1. Blend IBU and MCC in a plastic bag. Weigh 200 g for powderfeeding.

[0241] 2. Prewet IBU/MCC blend with 250 g water in a VG.

[0242] 3. Transfer prewetted blend into apparatus of Example 1.

[0243] 4. Set the parameter for processing as follows: Spray rate 35g/min

[0244] Four baffles (shallow)

[0245] Atomization air pressure 30%

[0246] Rotor speed (low) 300 rpm

[0247] 5. Spray˜700-1000 g of water

[0248] 6. Start powder feed at powder feed rate of 40. g/min. Reducespray rate to 20 g/min and continue spraying water.

[0249] 7. Finish spraying water, finish powder feed.

[0250] 8. Discharge the wet pellets. Dry in a GPCG-1 to moisture of <5%

[0251] Analytical Testing:

[0252] Dissolution of Ibuprofen from pellets (841-1190 micron), usingUSP dissolution testing at 60 min time point 47.3% Bulk density ofpellets (841-1190 micron) 0.70 g/cc

[0253] Process conditions: High rotor speed Ibuprofen (IBU) 100 g MCC(grade101) 900 g

[0254] 1. Blend IBU and MCC in a plastic bag. Weigh 200 g for powderfeeding.

[0255] 2. Prewet IBU/MCC blend with 250 g water in a VG.

[0256] 3. Transfer prewetted blend into the apparatus of Example 1.

[0257] 4. Set the parameter for the apparatus of Example 1 as follow:

[0258] 5. Spray rate 35 g/min.

[0259] Four baffles (shallow)

[0260] Atomization air pressure 30%

[0261] Rotor speed (high) 1000 rpm

[0262] 6. Spray˜700-1000 g of water.

[0263] 7. Start powder feed at powder feed rate of ˜40 g/min. Reducespray rate to 20 g/min and continue spraying water.

[0264] 8. Finish spraying water, finish powder feed.

[0265] 9. Discharge the wet pellets. Dry in a GPCG-1 to moisture of <5%

[0266] Analytical Testing:

[0267] Dissolution of Ibuprofen from pellets (841-1190 micron), usingUSP dissolution testing at 60 min time point 44.9% Bulk density ofpellets (841-1190 micron) 0.77 g/cc

[0268] Summary:

[0269] The processes without powder feeding step for low rotor speed andfor high rotor speed (Example 8) were compared to the processes withpowder feeding step for low rotor speed and for high rotor speed(Example 10). Other process parameters were kept constant so that theonly variable during the two processes is powder feeding step.

[0270] For Ibuprofen, which is a water insoluble compound, effect ofpowder feeding step on pellet shape and morphology was not as pronouncedas in the case of Chlorpheniramine maleate which is a water solublecompound.

[0271] The effect of powder feeding step on the Ibuprofen release ratewas very significant. This effect is more distinct for Ibuprofen (waterinsoluble compound) than Chlorpheniramine maleate (water solublecompound). At low rotor speed condition, the powder feeding step led toa significant decrease in Ibuprofen release from pellets (at 60 mintimepoint, 47.3% vs. 72.1% without powder feeding step). The bulkdensity of pellets produced using powder feeding step was slightlyhigher (0.70 g/cc vs. 0.66 g/cc without powder feeding step).

[0272] At high rotor speed condition, the powder feeding step led toslight increase in Ibuprofen release (at 60 min timepoint, 44.9% vs.38.6% without powder feeding step). The bulk density of pellets producedusing powder feeding step was slightly lower (0.77 g/cc vs. 0.88 g/ccwithout powder feeding step).

[0273] Dissolution Profiles of Ibuprofen Pellets (prepared at low rotorspeed, high rotor speed and low rotor speed with powder feeding).

[0274] The Ibuprofen pellets prepared in Example 8 and Example weresubmitted for dissolution-testing for 24 hours.

[0275] The dissolution profiles are summarized in Table 2. Dissolutionor Ibuprofens from Pellets Prepared at different process conditions LowRotor Low Rotor High Rotor Speed with Time Speed Speed powder feed(hours) (Ex. 8) (Ex. 8) (Ex. 10) 0.25 34.2 19.2 24.9 1 72.1 39.6 49.0 294.3 54.2 66.8 4 103.0 71.9 87.6 6 103.1 83.3 98.5 8 103.3 91.0 101.6 12103.5 97.5 101.9 18 103.4 97.7 102.2 24 103.7 98.1 102.3 Bulk 0.66 0.800.70 Density (g/cc)

[0276] Using Ibuprofen as an example of a water insoluble compound, itis possible to produce sustained release drug pellets by controlling theprocess conditions of the invention (low vs. high rotor speed) thataffect density of pellets which in turn affect drug release from thepellets.

[0277] The process of the invention allows the process parameters to beadjusted during pellet formation. These adjustments can affect physicalcharacteristics, as well as drug release, of pellets. It is possible toadd additional powder (after core pellets are formed). This addition ofpowder can affect pellets shape, morphology and release of drug from thepellets. The powder feeding step for Ibuprofen pellets, which is a waterinsoluble compound, affected the release rate significantly, especiallyat low rotor speed conditions. It is possible to produce sustainedrelease pellets by varying density of pellets being formed and byaddition of powder during processing.

1. A pellet which is adapted for use as a core for a pharmaceuticaldosage form, said pellet having an inner and an outer zone, said innerzone comprising a biologically active agent and said outer zonecomprises a layer which is formed by applying to said inner zone, asubstantially dry, free flowing inert powder which forms a non-tackysurface when placed in contact with water.
 2. A pellet as defined inclaim 1 wherein said free flowing, inert powder is a water insolublepowder.
 3. A pellet as defined in claim 1 wherein said free flowing,inert powder is selected from the group consisting of microcrystallinecellulose, dicalcium phosphate, calcium sulfate, talc, an alkali metalstearate, silicon dioxide and calcium carbonate.
 4. A pellet as definedin claim 1 wherein the inner zone comprises from 0.1-95wt % of one ormore pharmaceutically acceptable binders and or diluents and 99.9-5.0wt% of a biologically active agent.
 5. A pellet as defined in claim 1wherein said outer zone is formed from a powder which forms a non-tackysurface when placed in contact with water and from 0.1-99wt % of abiologically active agent.
 6. A pellet as defined in claim 1 whereinsaid outer zone is formed from a powder comprising microcrystallinecellulose and from 0.1-99wt % of a biologically active agent.
 7. Apellet as defined in claim 1 wherein said inner zone additionallycomprises one or more components selected from the group consisting oflubricants, disintegrants, flavors, surfactants, anti-sticking agents,osmotic agents and mixtures thereof.
 8. A pellet as defined in claim 1wherein said outer zone additionally comprises one or more componentsselected from the group consisting of binders, diluents, disintegrants,lubricants, flavors, surfactants, anti-sticking agents, osmotic agentsand mixtures thereof.
 9. A pellet as defined in any one of claims 1 or 2wherein said inner or outer zone comprises a swellable matrix formingpolymer.
 10. A pellet as defined in any one of claims 1 or 2 whereinsaid inner or outer zone comprises a non-swellable matrix formingpolymer.
 11. A pellet as defined in any one of claims 1 or 2 whereinsaid pellet is provided with a layer comprising a swellable matrixforming polymer and a non-swellable matrix forming polymer.
 12. A pelletas defined in any one of claims 1 or 2 having one or more layers whichcomprise a release rate controlling polymer.
 13. A pellet as defined inany claim 8 wherein said swellable polymer is selected from the groupconsisting of hydroxypropyl methyl cellulose, hydroxypropyl cellulose,hydroxyethyl cellulose and carboxypolymethylene.
 14. A pellet as definedin any claim 11 wherein said release rate controlling polymers areselected from the group consisting of ethyl cellulose, methacrylic acidcopolymers, cellulose acetate phthalate, hydroxypropylmethylcellulosephthalate, hydroxypropylmethylcellulose acetate succinate, celluloseacetate trimellitate and polyvinyl acetate phthalate.
 15. A process formaking pharmaceutical pellets as defined in claim 1 wherein said core orat least one of said layers is formed by (a) contacting powderparticles, adhering them to each other and compacting said adheredpellets by a rolling movement, wherein the degree of densification iscontrolled by the rolling movement; and (b) feeding a sufficient amountof a substantially dry, free flowing inert powder which forms anon-tacky surface when placed in contact with water to provide on saidparticles an outer zone comprising a layer formed from saidsubstantially dry, free flowing inert powder.
 16. A process for makingsolid pellets which are adapted for use as a pellet core for a dosageform which includes a biologically active agent, said processcomprising: (a) forming a powder mixture which comprises a binder and abiologically active agent; (b) feeding said powder mixture which isoptionally pre-wetted with from 0-60% of a pharmaceutically acceptablediluent, based on the total weight of the powder and thepharmaceutically acceptable diluent, to an operating apparatus whichcomprises a rotor chamber having an axially extending cylindrical wall,means for passing air through said chamber from the bottom, spray meansfor feeding a liquid into said chamber, a rotor which rotates on avertical rotor axis, said rotor being mounted in said rotor chamber,said rotor having a central horizontal surface and, in at least theradial outer third of said rotor, the shape of a conical shell with anoutward and upward inclination of between 10° and 80°, said conicalshell having a circularly shaped upper edge which lies in a plane whichis perpendicular to the rotor axis, feed ports for introducing saidpowdered excipient, a plurality of guide vanes having an outer endaffixed statically to said cylindrical wall of said rotor chamber abovea plane formed by the upper edge of said conical shell of said rotor andan inner end which extends into said rotor chamber and is affixedtangentially to said cylindrical wall of said rotor chamber and having,in cross-section to the rotor axis, essentially the shape of an arc of acircle or a spiral, such that said powdered product which is circulatedby kinetic energy by said rotor under the influence of kinetic energy,moves from said rotor to an inside surface of said guide vanes beforefalling back onto said rotor; (c) rotating said rotor, while feeding airand spraying a pharmaceutically acceptable liquid into said rotorchamber for a sufficient amount of time to form solid pellets having adesired diameter; and (d) feeding a sufficient amount of a substantiallydry, free flowing inert powder which forms a non-tacky surface whenplaced in contact with water to provide on said particles an outer zonecomprising a layer formed from said substantially dry, free flowinginert powder.
 18. A process as defined in claim 16 wherein in step (d)the dry powder has the same composition as the non-wetted powder that isfed in step (a).
 19. A process as defined in claim 16 wherein saidpowder mixture in step (a) comprises a biologically active agent and aninert powder that is selected from the group consisting ofmicrocrystalline cellulose, dicalcium phosphate, calcium sulfate, talc,an alkali metal stearate, silicon dioxide, calcium carbonate andmixtures thereof.
 20. A process as defined in claim 16 wherein thepowder mixture in step (a) comprises a biologically active agent and aninert powder that is microcrystalline cellulose.
 21. A process asdefined in claim 16 wherein the biologically ctive compound is selectedfrom the group consisting of vitamins, nutrients, pharmaceuticals andmixtures thereof.
 22. A process as defined in claim 16 wherein thebiologically active agent is a pharmaceutically active compound.
 23. Aprocess as defined in claim 16 wherein the pharmaceutically acceptableliquid diluent is water.
 24. A process for making discrete substantiallyspherical pellets comprising: (a) feeding, a powder which comprises abiologically active agent and a binder, said powder being pre-wettedwith from 5-60% of a pharmaceutically acceptable liquid diluent, basedon the total weight of the powder and the liquid diluent, to anoperating apparatus which comprises a rotor chamber having an axiallyextending cylindrical wall, means for passing air through said chamberfrom the bottom, spray means for feeding a liquid into said chamber, arotor which rotates on a vertical rotor axis, said rotor being mountedin said rotor chamber, said rotor having a central horizontal surfaceand, in at least the radial outer third of said rotor, the shape of aconical shell with an outward and upward inclination of between 10° and80°, said conical shell having a circularly shaped upper edge which liesin a plane which is perpendicular to the rotor axis, feed ports forintroducing said powdered excipient, a plurality of guide vanes havingan outer end affixed statically to said cylindrical wall of said rotorchamber above a plane formed by the upper edge of said conical shell ofsaid rotor and an inner end which extends into said rotor chamber and isaffixed tangentially to said cylindrical wall of said rotor chamber andhaving, in cross-section to the rotor axis, essentially the shape of anarc of a circle or a spiral, such that said powdered product which iscirculated by kinetic energy by said rotor under the influence ofkinetic energy, moves from said rotor to an inside surface of said guidevanes before falling back onto said rotor; and (b) rotating said rotor,while feeding air and spraying a pharmaceutically acceptable liquid intosaid rotor chamber for a sufficient amount of time to form substantiallyspherical pellets having a desired diameter; and (c) feeding asufficient amount of a dry powder which comprises a biologically activeagent and a binder or a free flowing inert powder which forms anon-tacky surface in contact with water to form an outer layer on saidsubstantially spherical pellets.
 25. A process as defined in claim 24wherein in step (c) dry powder in an amount that is equivalent to 5 to35 wt. % of the wetted powder that was initially fed to the apparatus,is added and the apparatus is allowed to run for a period of time toform said outer layer.
 26. A process as defined in claim 24 wherein saidpowder which comprising a biologically active agent includesmicrocrystalline cellulose and optionally comprises one or morecomponents selected from the group consisting of binders, diluents,lubricants, disintegrants, flavors, surfactants, anti-sticking agents,osmotic agents and mixtures thereof.
 27. A process as defined in claim24 wherein the biologically active compound is selected from the groupconsisting of vitamins, nutrients, pharmaceuticals and mixtures thereof.28. A process as defined in claim 24 wherein the biologically activeagent is a pharmaceutically active compound.
 29. A process as defined inclaim 24 wherein the pharmaceutically acceptable liquid diluent iswater.
 30. A pharmaceutical dosage form which comprises coated pelletshaving as a core a pellet as defined in claim 1 and one or more releaserate controlling coatings selected from the group consisting of delayedrelease coatings and sustained release coatings or mixtures thereof. 31.A pharmaceutical dosage form as defined in claim 30 wherein thecontrolled release coating is a sustained release coating.
 32. Apharmaceutical dosage form as defined in claim 30 wherein the controlledrelease coating is a delayed release coating.
 33. A pharmaceuticaldosage form as defined in claim 30 wherein the dosage form includesdifferent populations of coated pellets having different controlledrelease coatings.
 34. A pharmaceutical dosage form as defined in claim30 wherein the dosage form is a hard gelatin capsule.